This proposal brings together experts in the genetics of mood disorders from the Johns Hopkins University (JHU) School of Medicine and translational neuroscience from the Lieber Institute for Brain Development to investigate the genetic underpinnings of bipolar disorder (BP). Recent meta-analysis of genome-wide association studies (GWAS) of BP conducted by the Psychiatric Genomics Consortium (PGC) have led to the strongest credible reports of genetic associations with the disorder. However, the neurobiological mechanisms by which the implicated variants increase the risk for BP are unknown. In addition, the genetic variants identified thus far explain only a small proportion of the heritability of BP, indicating that the bulk of causal variants and the molecular pathways they are involved in remain unknown. The Lieber Institute, which specializes in the neuro-developmental origins of mental disorders in order to elucidate biological mechanisms of illness and motivate new treatments, has amassed one of the largest collections in the world of post-mortem brain samples from psychiatric patients and non-mentally ill control subjects. These samples have been extensively characterized clinically, genetically, and molecularly. As a result, they provide a unique resource for examining the neurobiological mechanisms by which genetic factors contribute to mental disorders directly in the primary affected tissue. We seek to integrate findings from GWAS by the PGC and RNA-sequencing of the transcriptomes of the Lieber brain samples to elucidate the genetic basis of BP. The specific aims of the proposal are to: 1) Carry out RNA-sequencing of the amygdala and subgenual anterior cingulate cortex in 120 BP cases and 180 matched non-mentally ill controls from the Lieber brain sample collection (RNA-sequencing of the dorsolateral pre-frontal cortex and hippocampus from these samples is being completed as part of another project at no cost to the NIH, and we will add to this impressive resource data from key regions of the limbic system which are thought to be centrally involved in BP); 2) Test whether genome-wide significant SNPs identified from the PGC GWAS of BP are associated with mRNA expression, splicing, or long non-coding RNA expression across the key regions of the brain; 3) Test for differential expression at the exon, gene and transcript levels in key regions of the brain of BP case versus non-mentally ill controls, and use the results to examine if differentially expressed genes and their involved pathways are enriched for genetic associations with BP in the PGC GWAS data; and 4) Make the primary data and results from this project freely available via an online data resource. By identifying new genetic associations with BP and explicating the mechanisms by which they increase risk, we aim to provide novel targets for intervention in the disease process and, therefore, a more rational basis for improved treatments.